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bioRxiv · 10.1101/2024.12.17.628820

Assessing the efficacy of therapeutically promising combination of polymyxin B and triclosan against colistin resistant Klebsiella pneumoniae

Biswas, S.·Ghosh, S.·Patra, S. D.·Mahapatra, P.·Verma, G.·Misra, N.·Kushwaha, G. S.·Suar, M.
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Abstract

Antimicrobial resistance (AMR) is one of the greatest public health challenges of the current time, and it is primarily associated with Gram-negative bacterial infections. Among these infections, Klebsiella pneumoniae is the most notorious bacterial pathogen in the context of AMR dissemination. In this dire circumstance, clinicians explored old regimes such as colistin to treat these multidrug-resistant infections; however, unfortunately, the resistance towards these last-resort drugs is also emerging rapidly. In this study, we examined the occurrence of colistin resistance in K. pneumoniae concerning its mechanism of resistance, chronology, and geographical distribution. We found that resistance towards these last-resort drugs, colistin and polymyxin B, is emerging rapidly, with evolving multiple mechanisms of resistance. While efforts continue to develop new antibacterial drugs, a combination of approved antibacterial drugs may be one of the most suitable strategies to fight against AMR in the current time-ticking situation. In this series, we evaluated the efficacy of a therapeutically viable combination of polymyxin B and triclosan using a set of standard antibacterial assays, used for in vitro preclinical efficacy. We found that the combination is highly effective in colistin-resistant clinical strains of K. pneumoniae, as triclosan sensitizes the pathogen towards polymyxin B. Furthermore, the results of additional complementary experiments, such as time-kill kinetics, biofilm inhibition, frequency of resistance, cell viability, and cytotoxicity assays, show very encouraging results for the feasibility and validation of this combination. Finally, we examined the presence of mutations in field isolates of K. pneumoniae FabI enzyme, as it has been hypothesized previously that triclosan may cause mutation in its binding target, FabI. Interestingly, we could not detect any mutation in the triclosan binding site of FabI in the genome of field isolates. Altogether, this study provides an overview of the current situation on colistin resistance, a promising solution for colistin resistance comprising a combination of two already being used antibacterial ingredients based on in vitro efficacy studies.

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Biswas, S., Ghosh, S., Patra, S. D., Mahapatra, P., Verma, G., Misra, N., Kushwaha, G. S., Suar, M.. 2024-12-18. Assessing the efficacy of therapeutically promising combination of polymyxin B and triclosan against colistin resistant Klebsiella pneumoniae. https://doi.org/10.1101/2024.12.17.628820

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